Described originally as Epithelial Specific ETS (ESE)-1 (Elf3 in mouse), we have found that this novel transcription factor suppresses type II collagen gene (COL2A1) expression by binding to the COL2A1 promoter and interacting with Sox9 and CBP and that ESE-1 immunostaining is increased in superficial and midzone regions of cartilage from patients with osteoarthritis (OA). Our preliminary data show that ESE-1 increases the transcription of matrix metalloproteinase (MMP)-13 by binding to ETS/PEA3 sites in the MMP13 promoter and cooperating with Runx2 and AP-1. The absence of MMP-13 protein in the Ese1/Elf3-deficient mouse and the increased Ese1 expression in the articular cartilage of the cho/+ mouse model of OA compared to wild type mice further suggest its pivotal role in de-regulated cartilage remodeling during OA. Thus, we hypothesize that ESE-1 is a critical transcriptional regulator of cartilage remodeling during OA progression. The Specific Aims are: (1) What are the signaling pathways that induce and activate ESE-1 to regulate MMP-13 and other targets? We will use primary mouse and human chondrocytes and cell lines to characterize the signaling and transcriptional mechanisms involved in the induction and action of ESE-1 in the regulation of MMP13 and other gene targets, including the structure/function relationships that determine ESE-1 actions under basal and inflammatory conditions. (2) Does Ese1/Elf3-deficiency protect against or attenuate cartilage loss in surgical and genetic mouse models of OA, and if so, what are its mechanisms of action? We will employ Ese1/Elf3 knockout mice subjected to non-genetic experimentally induced (surgical) OA and the Cho/+ mouse model of age-dependent OA and map gene expression during onset and progression of OA by sensitive, in situ gene expression analysis and other techniques developed in Aim 1. (3) Does ESE-1 over-expression affect the onset or progression of OA in mouse knee joints due to aging or surgical OA? We will generate Tet-Off-inducible Ese1 transgenic mice to examine whether excess ESE-1, by itself, initiates or accelerates surgically induced OA and reveal if ESE-1-dependent mechanisms correlate with the extent of OA progression. By applying insights from in vitro studies to the analysis of early and late events by ex vivo and in situ approaches in the mouse models, we will gain understanding of molecular events underlying initiation and progression that will lead to the development of novel targeted therapies for OA due to trauma or aging.